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  • Fei-fei LIU, Dong LIU, Dong LI, Yu-zhu WANG
    Chinese Journal of Clinical Pharmacology. 2025, 41(18): 2692-2696.

    The research and development of combination chemical drug occupy an important position in the development of new drugs and generic drugs. Two or more active ingredients are often formulated into combined preparations for development based on clinical needs, the mechanism of drug action and actual clinical effects. In the research and development of combined chemical drugs, clinical pharmacology research serves as a crucial bridge connecting the theories of drug research and development and the practical application in clinical practice. Based on regulations and guidelines, this article explores the application of clinical pharmacology research in the research and development of combined pharmaceutical preparations by integrating research and development cases, clinical practice and literature research.

  • Ming-li HENG, Feng-yu SUN, Chen-bo ZHANG
    Chinese Journal of Clinical Pharmacology. 2025, 41(18): 2697-2700.

    The purpose of this article is to discuss the general statistical considerations of confirmatory clinical trial design of antiviral drugs for uncomplicated influenza patients, including estimands, sample size, bias control measures and statistical analysis methods, with reference to the Food and Drug Administration (FDA) biostatistics review report on baloxavir marboxil, the guidance of clinical trial technology for influenza treatment and prevention drugs, ICH E9R1 and statistical guidances issued by National Medical Products Administration (NMPA), in order to provide reference for clinical trial design of antiviral drugs in uncomplicated influenza patients.

  • Zhi-hua WANG, Min LI, Jun-de DENG, Rui CHENG
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2401-2406.
    Objective

    To analyze the clinical efficacy and safety of polyenophosphatidylcholine (PPC) in combination with tenofovir tablets in the treatment of patients with hepatitis B combined with nonalcoholic steatohepatitis (NASH).

    Methods

    The patients with hepatitis B complicated with NASH in our hospital were divided into treatment group and control group by random number table method. The control group was treated with tenofovir tablets, 25 mg qd, taken during meals. The treatment group was treated with PPC on the basis of the control group. The initial dose was 456 mg tid, taken with warm boiled water, and the daily dose could not exceed 1 368 mg. After 12 weeks of treatment, the dose was reduced to 228 mg tid, according to the immune response, and the dose was maintained. Both groups were treated for 24 weeks, and the treatment group was followed up to 48 weeks after stopping PPC. The negative conversion rates of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg), hepatitis B virus DNA (HBV-DNA) load, the levels of costimulatory molecule B7 homolog 1 (B7-H1), transforming growth factor β1 (TGFβ1), Golgi transmembrane glycoprotein 73 (GP73), chitinase 3-like protein 1 (CHI3L1) and prothrombin activity (PTA) were compared between the two groups, and the safety was evaluated.

    Results

    A total of 95 cases were enrolled and 92 cases were included in statistical analysis, including 46 cases in the treatment group and 46 cases in the control group. After treatment, the total effective rates of the treatment group and the control group were 97.83% (45 cases / 46 cases) and 84.78% (39 cases / 46 cases), respectively, and the difference was statistically significant (P<0.05). After 24 weeks of treatment, the HBV-DNA load of the treatment group and the control group were 80.43% and 60.87%, respectively; the HBsAg negative conversion rates were 28.26% and 10.87%, respectively; and the HBeAg negative conversion rates were 30.43% and 13.04%, respectively. The above indicators in the treatment group were statistically significantly different from those in the control group (all P<0.05). After 48 weeks of treatment, the HBV-DNA load of the treatment group and the control group were 89.13% and 69.57%, respectively; the HBsAg negative conversion rates were 50.00% and 28.26%, respectively; and the HBeAg negative conversion rates were 50.00% and 26.09%, respectively. The above indicators in the treatment group were statistically significantlly different from those in the control group (all P<0.05 ). After treatment, the levels of B7-H1 in the treatment group and the control group were 0.40 (0.30, 0.40) and 0.60 (0.50, 0.70) ng·mL-1, the levels of TGFβ1 were (269.02±24.36) and (287.64±27.39) ng·mL-1, respectively; and the levels of GP73 were (76.24±8.95) and (87.22±10.03) ng·mL-1, respectively; PTA were (80.02 ± 12.55)% and (65.24±10.24)%, respectively. The treatment group compared with the control group, the differences were statistically significant (all P<0.05). The main adverse drug reactions during treatment in the treatment group and the control group were nausea and vomiting, headache, rash and abdominal distension. The total incidence of adverse drug reactions in the treatment group was 10.87% (5 cases / 46 cases), which was 13.04% (6 cases / 46 cases) in the control group, and the difference had no statistically significant (P>0.05).

    Conclusion

    The combined application of PPC and tenofovir tablets in the treatment of hepatitis B patients with NASH can reduce the levels of B7-H1 and TGFβ1, improve the liver function of the body, and has good safety.

  • Li-shan ZHU, Wen-xin GAO, Jia-ying LI, Jing LIANG
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2407-2411.
    Objective

    To develop and validate a simple scoring system for predicting the risk of infection after acute myocardial infarction (AMI) in patients undergoing percutaneous coronary intervention (PCI).

    Methods

    Continuous patients with ST-segment elevation myocardial infarction (STEMI) who received PCI in our hospital were divided into training set and validation set using a cohort approach. All patients received oral rosuvastatin calcium tablets 10-20 mg per day combined with evolocumab injection therapy 140 mg. The primary endpoint was post-AMI infection during hospitalization, while all-cause mortality and major adverse cardiovascular events (MACE) were considered secondary endpoints. The area under the curve (AUC) and the calibration between predicted and observed infection risks were calculated. A backward stepwise logistic regression model was selected to develop the risk score.

    Results

    A total of 359 patients were included, with 217 in the training set and 142 in the validation set, and no patient dropout occurred during the study. A 24-point risk scoring system was developed, with infection risks ranging from 0.70% to 99.60% in patients with the lowest and highest scores, respectively. Seven variables including age, Killip class, insulin use, white blood cell count, serum albumin, diuretics and transfemoral approach were incorporated into the model. The model achieved equally high discrimination in both the development and validation cohorts (C-statistic: 0.85) and demonstrated good calibration in both datasets. In both development and validation cohorts, the incidence of post-myocardial infarction infection increased steadily across risk score groups. Additionally, this risk score exhibited good predictive ability for infection, in-hospital all-cause mortality.

    Conclusion

    This study established a simple bedside tool, a risk scoring system for assessing the risk of infection and other in-hospital outcomes in STEMI patients undergoing PCI. Clinicians can utilize this risk scoring system to evaluate infection risk and make evidence-based decisions accordingly.

  • Song-ze LIU, Rui-tong LI, Zi-yi CHEN, Si-yuan TANG, Xiao-xu ZHANG, Rui-na REN, Xue-ding WANG, Min HUANG
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2412-2417.
    Objective

    To investigate the association between drug resistant epilepsy (DRE) and single nucleotide polymorphisms (SNPs) in whole-exome sequencing (WES).

    Methods

    Patients with epilepsy, who visited in our hospital, were enrolled in this study and divided into a drug-resistant group and a monotherapy-effective group based on treatment outcomes. Baseline demographic characteristics, medical history and laboratory test results were collected. Seizure outcomes were observed after more than 12 months under adequate treatment. WES was performed on 12 extreme cases (6 patients with resistant to three antiepileptic drugs vs. 6 patients effectively treated with monotherapy and undergoing dose reduction) to identify candidate SNPs. These candidate SNPs were then validated in the larger cohort to explore the association with DRE.

    Results

    A tota of 560 patients were enrolled, 153 were DRE group and 407 were monotherapy-effective group. The median age in the monotherapy-effective group and the drug-resistant group was 19 years old and 25 years old, respectively; the median weight were 50 kg and 55 kg, respectively. All these differences between the two groups were statistically significant (all P<0.05); the proportion of structural etiology was 55.56% in the drug-resistant group and 45.46% in the monotherapy-effective group; the proportion of infectious etiology were 3.92% and 2.21%; the proportion of immune etiology were 3.27% and 1.23%; the proportion of metabolic and genetic etiology were 5.88% and 11.30%; the proportion of dual etiologies were 1.96% and 1.23%; the proportion of patients with impaired consciousness were 56.21% and 39.07%; the proportion of second-generation antiseizure medication as initial medication regimen were 50.98% and 65.46%; the proportion of malformation of cortical development were 10.46% and 2.95%; the proportion of hippocampal sclerosis were 15.03% and 9.58%; the proportion of hypoxic-ischemic encephalopathy were 3.92% and 1.47%; the proportion of vascular malformation were 4.58% and 3.93%; the proportion of traumatic brain injury were 1.31% and 3.44%; the proportion with brain tumor were 3.92% and 2.21%; the proportion with dual pathologies were 1.96% and 0.98%; the proportion of abnormal nonepileptogenic were 23.53% and 29.48%. Baseline information showed statistically significant differences in age, weight, etiology, presence of impaired awareness, initial medication regimen and neuroimaging results (P<0.05, P<0.001). 102 candidate SNPs were selected for genotyping and association analysis in larger cohort including 560 patients. 5 SNPs were identified to be significantly associated with DRE. Multivariate logistic regression incorporating both clinical and genetic factors revealed that hippocampal sclerosis, malformation of cortical development, hypoxic-ischemic, presence of impaired awareness, as well as the SCN2A rs17183814 GG and SPATA31 rs1919128 GA genotypes were risk factors for drug resistance (SCN2A rs17183814 GG: P=0.027; SPATA31 rs1919128 GA: P=0.014).

    Conclusion

    SCN2A rs17183814 and SPATA31 rs1919128 were found to be associated with drug resistance. Carriers of the GG genotypes of SCN2A rs17183814 and GA genotype of SPATA31 rs1919128 are more likely to develop DRE.

  • Guo-biao LI, Cai-yun WU, Zi-qing GONG
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2418-2422.
    Objective

    To observe the effects of empagliflozin tablets-assisted therapy on end-diastolic volume and major cardiovascular adverse events in patients with mild reduced EF heart failure (HFmrEF).

    Methods

    Patients with HFmrEF were divided into control group and treatment group by queue method. The control group received conventional treatment. The treatment group was given empagliflozin tablets in addition to control group, 10 mg each time (starting dose and target dose were both 10 mg), orally on an empty stomach in the morning, once a day. Both groups of patients were treated for 6 months. The clinical efficacy, end-diastolic volume including left ventricular end-diastolic area (LVEDA) and left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), myocardial markers including cardiac troponin I (cTnI) and N-terminal B-type natriuretic peptide (NT-proBNP), major adverse cardiovascular events and safety were compared between the two groups.

    Results

    Both groups had no cases dropped out, with 60 cases in control group and 60 cases in treatment group. After treatment, the total effective rates of treatment group and control group were 95.00% (57 cases/60 cases) and 81.67% (49 cases/60 cases), respectively, with statistically significant difference (P<0.05). After treatment, the LVEF of treatment group and control group were (56.20±5.12)% and (50.25±4.26)%, LVEDV were (142.58±15.58) and (165.28±18.59) mL, LVEDA were (36.28±3.41) and (39.62±3.56) cm2, serum NT-proBNP levels were (869.48±135.29) and (1 459.87±158.69) pg·mL-1, cTnI levels were (7.02±1.65) and (9.28±1.74) ng·L-1, respectively, and the incidence of major cardiovascular adverse events in treatment group and control group were 5.00% and 16.67%. The above indexes in treatment group had statistical significant differences compared with control group (all P<0.05). The adverse drug reactions of treatment group mainly include headache, hyperkalemia, hypotension and gastrointestinal reactions, while the adverse drug reactions of control group mainly include hyperkalemia, headache and hypotension. During the treatment, the incidence of adverse drug reactions in treatment group and control group were 8.33% and 5.00%, respectively (P>0.05).

    Conclusion

    Adjuvant treatment with empagliflozin tablets can improve the overall therapeutic effect of HFmrEF, improve the end diastolic volume index and LVEF of patients, regulate myocardial marker indicators, reduce the incidence of major cardiovascular adverse events, and has good safety.

  • Chong-xin WANG, Yue-yue ZHENG, Xiao-xia SHI
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2423-2428.
    Objective

    To explore the clinical efficacy and safety of beraprost sodium tablets combined with alprostadil injection in patients with stage Ⅲ diabetic nephropathy.

    Methods

    According to queuing method, inpatients with stage Ⅲ diabetic nephropathy treated in the hospital were divided into treatment group and control group. Treatment group was treated with beraprost sodium tablets + alprostadil injection (the first 2 weeks: intravenous drip of alprostadil injection 10 μg qd. the last 2 weeks: oral beraprost sodium tables 40 μg tid), while control group was treated with alprostadil injection (the same administration method as treatment group for 4 weeks). The clinical efficacy, β2 microglobulin (β2-MG), cystatin C (Cys-C), blood urea nitrogen (BUN), serum creatinine (SCr), urinary albumin to creatinine ratio (UACR), transforming growth factor β1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), hemoglobin Alc (HbAlc), fasting blood glucose (FBG), 2 h postprandial blood glucose (2 h PBG), homeostasis model assessment for insulin resistance (HOMA-IR), hypersensitive C-reactive protein (hs-CRP), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were compared between the two groups, and the safety was evaluated.

    Results

    Among the 103 patients, there were 52 cases in treatment group and 51 cases in control group. The efficiency rate in treatment group was higher than that in control group [92.31% (48 cases/52 cases) vs. 78.43% (40 cases/51 cases), P<0.05]. After treatment, levels of serum β2-MG in treatment group and control group were (0.25±0.06) and (0.31±0.07) mg·L-1, BUN levels were (5.70±0.91) and (6.89±1.01) mmol·L-1, SCr levels were (85.46±8.89) and (93.88±9.77) μmol·L-1, Cys-C levels were (1.38±0.26) and (1.64±0.30) mg·L-1, UACR levels were (140.24±31.04) and (176.40±36.19) mg·g-1, respectively; levels of serum TIMP-1 were (88.34±12.36) and (97.62±15.44) ng·mL-1, TGF-β1 levels were (112.49±17.24) and (138.50±19.84) ng·mL-1, MMP-9 levels were (130.69±21.30) and (114.79±19.77) μg·L-1, respectively; levels of serum IL-6 were (141.49±28.85) and (173.49±32.36) pg·mL-1, hs-CRP levels were (7.64±1.16) and (9.29±1.54) mg·L-1, TNF-α levels were (23.65±4.34) and (29.12±3.86) pg·mL-1, and differences in the above indexes between treatment group and control group were all statistically significant (all P<0.05). During treatment, there was 1 case with diarrhea, 1 case with rash and 1 case with nausea and vomiting in treatment group, while there was 1 case with rash and 1 case with diarrhea in control group. There was no statistically significant difference in incidence of adverse drug reactions between treatment group and control group (5.77% vs. 3.92%, P>0.05).

    Conclusion

    Alprostadil injection combined with beraprost sodium tablets can effectively improve renal function, regulate metabolism of extracellular matrixes in renal tissues, relieve inflammatory response and improve clinical curative effect in patients with stage Ⅲ diabetic nephropathy.

  • Qing MA, Li LI, Shan-shan ZHU, Qiao-yan WANG, Hao CHEN
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2429-2434.
    Objective

    To investigate the clinical efficacy and safety of midazolam injection combined with propofol medium/long-chain fat emulsion target-controlled infusion (TCI) in severely obese patients undergoing laparoscopic sleeve gastrectomy with double-tract anastomosis (LSG-DJB).

    Methods

    Severely obese patients treated in our hospital were randomly assigned by a random number table method to the control group or the treatment group. The control group received propofol medium/long-chain fat emulsion TCI (effect-site concentration 1.2–2.0 μg·mL-1), while the treatment group additionally received midazolam injection (0.03 mg·kg-1 for induction, 0.02 mg·kg-1·h-1 for maintenance). Pain indicators, recovery quality, inflammatory markers, oxidative stress parameters and safety outcomes were compared between the two groups.

    Results

    A total of 179 patients were screened in this study, with 67 cases enrolled in the control group and 68 cases in the treatment group. Three cases dropped out in the control group and four cases dropped out in the treatment group; ultimately, 64 cases in each group completed the study. The pain scores (NRS) at discharge from the operating room were (0.76±0.42) and (0.93±0.28) points for the treatment group and control group, respectively; at 6 hours postoperatively, they were (1.94±0.46) and (2.37±0.82) points, respectively; at 12 hours postoperatively, they were (2.24±0.51) and (2.92±0.71) points, respectively. Compared with the control group, the differences in the above indicators in the treatment group were statistically significant (all P<0.05). The total intraoperative dosage of sufentanil injection were (0.75±0.12) and (0.92±0.15) μg·kg-1 for the treatment group and control group, respectively; the eye-opening time was (10.77±1.48) and (8.39±1.23) min, respectively; the extubation time was (18.68±2.91) and (13.21±2.48) min, respectively; the respiratory recovery time was (16.87±2.25) and (11.93±2.03) min, respectively. Compared with the control group, the differences in the above indicators in the treatment group were statistically significant (all P<0.05). At 24 hours postoperatively, the serum interleukin-6 (IL-6) levels were (72.16±10.28) and (88.32±11.14) ng·L-1 for the treatment group and control group, respectively; tumor necrosis factor-α (TNF-α) levels were (152.47±21.95) and (176.84±25.67) ng·L-1, respectively; C-reactive protein (CRP) levels were (5.63±0.88) and (7.74±0.86) mg·L-1, respectively; malondialdehyde (MDA) levels were (4.82±1.19) and (7.03±1.22) mmol·mL-1, respectively; cortisol (Cor) levels were (31.42±3.27) and (37.75±4.16) μg·dL-1, respectively; superoxide dismutase (SOD) levels were (37.38±5.82) and (23.67±3.59) mmol·mL-1, respectively. Compared with the control group, the differences in the above indicators in the treatment group were statistically significant (all P<0.05). The main adverse drug reactions in the treatment group were hypoxemia, hypotension, delayed recovery, nausea and vomiting; the main adverse reactions in the control group were nausea and vomiting, hypoxemia, and hypotension. The total incidence rates of adverse drug reactions were 54.69% and 42.19% in the treatment group and control group, respectively, with no statistically significant difference (P>0.05).

    Conclusion

    Midazolam injection combined with propofol medium/long-chain fat emulsion TCI provides optimized sedation depth, reduces inflammatory and stress responses, and demonstrates good safety in severely obese patients undergoing LSG-DJB.

  • Hai-rui CAI, An-er Chen
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2435-2440.
    Objective

    To compare the clinical efficacy and safety of labetalol injection and nifedipine controlled-release tablets combined with magnesium sulfate injection and calcium carbonate D3 tablets in the treatment of preeclampsia.

    Methods

    The patients with preeclampsia who were hospitalized in the obstetrics department of our hospital were included as the research objects, and the patients were divided into group A, group B and group C according to the medication plan. Group A was treated with labetalol hydrochloride injection 100-200 mg, intravenous drip, 1.5-3.5 mg per minute, once a day combined with 25% magnesium sulfate injection 60 mL, intravenous drip, 1.55-2.0 g per hour, 25 g per day and calcium carbonate D3 tablets, take orally, 300 mg each time, twice a day; Group B was treated with nifedipine controlled-release tablets orally, 30 mg each time, once a day, and the administration methods of magnesium sulfate injection, calcium carbonate D3 tablets were the same as those in group A; Group C was treated with labetalol hydrochloride injection, nifedipine controlled-release tablets, magnesium sulfate injection and calcium carbonate D3 tablets, and the administration methods of them were the same as those in group A and group B. The clinical efficacy, blood pressure condition, heart and kidney function, psychological status, fetal hemodynamics, maternal and pregnancy outcome of patients in 3 groups were compared, and the safety was evaluated.

    Results

    A total of 170 patients were enrolled, 90 patients in group A, 39 patiets in group B and 41 patients in group C. After treatment, the total effective rates of group A, Group B and Group C were 58.89% (53 cases/90 cases), 53.85% (21 cases / 39 cases) and 85.37% (35 cases / 41 cases), respectively, and the blood pressure recovery time were 3.00 (3.00,5.00), 3.00 (3.00,5.00), and 7.00 (3.00,9.00) d, respectively. The total effective rate of group C was statistically significantly higher than that of group A and group B (all P<0.05), and the recovery time of blood pressure was statistically significantly shorter than that of group A and group B (all P<0.05). After treatment, the systolic blood pressures of group A, group B and group C were (145.60±5.15), (143.72±4.86) and (137.24±5.07) mmHg, respectively; the diastolic blood pressures were (97.83±6.56), (96.72±7.00) and (86.80±4.87) mmHg, respectively; Hamilton anxiety scale scores were 15.00 (13.00,17.00), 15.00 (13.50,17.50) and 12.00 (11.00,14.00) points, respectively; the Hamilton depression scale scores were 14.00 (12.00,15.00), 14.00 (12.00,15.00) and 10.00 (9.00,12.00) points, respectively; and the above indicators in group C were all lower than those of group A and group B (all P<0.05). After treatment, the B-type natriuretic peptide levels in group A, group B and group C were 35.00 (21.00,56.00), 42.00 (22.50,90.50) and 24.00 (13.00,60.00) pg·L-1, respectively; the the urinary protein levels were 0.35 (0.14,0.57), 0.24 (0.15, 0.39) and 0.14 (0.06,0.34) g, respectively; and the B-type natriuretic peptide level of group C was statistically significantly lower than that of group B (P<0.05), and the urinary protein level was statistically significantly lower than that of group A (P<0.05). After treatment, the diastolic flow velocity ratio in group A, Group B and group C were 2.15 (1.92, 2.24), 2.04 (1.86, 2.23), 2.16 (2.02, 2.25), respectively; the flow resistance index were 0.53 (0.48, 0.55), 0.51 (0.46, 0.56), 0.54 (0.51, 0.58), respectively; the flow pulse index were 0.77 (0.66, 0.83), 0.69 (0.63, 0.80), 0.77 (0.67, 0.81), respectively; the incidence rates of adverse drug reactions were 13.33% (12 cases / 90 cases), 12.82% (5 cases / 39 cases) and 12.20% (5 cases / 41 cases), respectively; and there were no statistically significant differences in the above indicators and pregnancy outcome among the three groups (all P>0.05).

    Conclusion

    The therapy with labetalol, nifedipine, magnesium sulfate and calcium in PE is better, which can improve the blood pressure level, psychological status, heart and kidney function, maternal and infant outcomes, regulate fetal hemodynamics, and will not cause serious adverse reactions.

  • Shuang BAO, Shan-shan LIU, Yan-nan ZANG, Fei JIA, Xiao-qian LAN, Hong-yan ZHUANG, Meng-xi NIU, Peng-fei LI
    Chinese Journal of Clinical Pharmacology. 2025, 41(17): 2441-2445.
    Objective

    To investigate the off-label drug use of escitalopram in children and adolescents, and to provide a reference for rational clinical medication.

    Methods

    Collected prescription data of children and adolescents (<18 years) receiving antidepressant treatment, including gender, age, clinical diagnosis, drug name, dosage, frequency and route of administration. Based on domestic drug labeling, we assessed whether escitalopram was used off-label, and further conducted evidence-based searches regarding its off-label drug use. A literature search was conducted using the keywords escitalopram, off-label use, evidence-based medicine, children and adolescents across multiple electronic databases, including PubMed, Embase, The Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and VIP.

    Results

    This study included a total of 156 504 outpatients, with escitalopram prescribed to 9 798, the off-label use rate was 6.26%. An analysis of the off-label use of escitalopram was conducted based on 22 articles, including the original drug instructions, evidence-based databases and related medical literature, the results demonstrated that escitalopram was supported by evidence for the use of both depression and generalized anxiety disorder in children and adolescents.

    Conclusion

    Escitalopram has preliminary evidence-based support for its use in children and adolescent patients, it is an off-label application. Therefore, clinical practice should strengthen the supervision and management of off-label use of escitalopram to ensure medication safety for patients.